New substituted pyridine or piperidine compounds

ABSTRACT

The invention relates to a compound of formula (I):  
                 
 
     wherein  
     A represents pyridine, pyridinium or piperidine  
     R 1 , R 2 , R 3  and R 4  are as defined in the description  
     R 5  represents hydrogen, a nitrogen-containing heterocycle or a group of formula (II):  
                 
 
     R 6  represents hydrogen or linear or branched (C 1 -C 6 )alkyl.  
     and medicinal products containing the same which are useful in treating pain or deficiencies in memory.

FIELD OF THE INVENTION

[0001] The present invention relates to new substituted pyridine orpiperidine compounds and to their use as facilitators of memory andcognition and as antalgic agents.

BACKGROUND OF THE INVENTION

[0002] Ageing of the population due to increased life expectancy hasbrought with it a major increase in cognitive disorders associated withnormal cerebral ageing and with pathological cerebral ageing occurringin the course of neurodegenerative diseases such as, for example,Alzheimer's disease.

[0003] The majority of substances used today in treating cognitivedisorders associated with ageing act by facilitating the centralcholinergic systems—either directly, as in the case ofacetylcholinesterase inhibitors (tacrine, donepezil) and cholinergicagonists (nefiracetam), or indirectly, as in the case of nootropicagents (piracetam, pramiracetam) and cerebral vasodilators(vinpocetine).

[0004] Besides their cognitive properties, substances acting directly onthe central cholinergic systems often have antalgic properties but alsohave hypothermic properties, which can be undesirable.

[0005] It has been therefore been especially valuable to synthesise newcompounds that are capable of opposing the cognitive disordersassociated with ageing and/or of improving cognitive processes and thatcan possess antalgic properties without having hypothermic activity.

DESCRIPTION OF THE PRIOR ART

[0006] The literature discloses substituted piperidine compounds whichare described as products of synthesis and/or of alkaloids (J. Chem.Soc., Perkin Trans. 1, 1991, (3), pp. 611-616; Heterocycles, 1985, 23(4), pp. 831-834; Can. J. Chem., 1996, 74 (12), pp. 2444-2453).

[0007] Substituted pyridine compounds have also been described withreference to their synthesis (J. Chem. Soc., Dalton Trans., 1998, (6),pp. 917-922) or their interactions in metal complexes (J. Chem. Soc.,Chem. Commun. 1987, (19), pp. 1457-1459; J. Am. Chem. Soc., 1985, 107(4), pp. 917-925).

[0008] The compounds of the present invention are new and haveproperties that, from a pharmacological point of view, are especiallyvaluable.

DETAILED DESCRIPTION OF THE INVENTION

[0009] More specifically, the present invention relates to compounds offormula (I):

[0010] wherein:

[0011] A represents a pyridine, pyridinium or piperidine group,

[0012] R₂ represents a hydrogen atom and R₃ represents a hydroxy group,or R₂ and R₃ together form an oxo group,

[0013] R₄ represents an unsubstituted or substituted phenyl group, anunsubstituted or substituted naphthyl group or an unsubstituted orsubstituted heteroaryl group,

[0014] R₁ represents a hydrogen atom,

[0015] or R₁ and R₄, together with the two carbon atoms carrying them,form a ring containing 6 carbon atoms,

[0016] or R₁ and R₂ form an additional bond and, in that case, R₃represents a 5- or 6-membered heterocycle that contains a nitrogen atomby which it is bound and that may contain another hetero atom selectedfrom sulphur, oxygen and nitrogen,

[0017] R₅ represents

[0018] a 5- or 6-membered heterocycle that contains a nitrogen atom bywhich it is bonded to the ring A and that may contain another heteroatom selected from sulphur, oxygen and nitrogen,

[0019] a group of formula (II):

[0020] wherein R′₁, R′₂, R′₃ and R′₄ may have the same meanings as R₁,R₂, R₃ and R₄, respectively,

[0021] or a hydrogen atom and, in that case, R₄ cannot represent anunsubstituted phenyl group, an unsubstituted naphthyl group or anheteroaryl group,

[0022] R₆ represents a hydrogen atom or a linear or branched(C₁-C₆)alkyl group, the group R₆ being present or absent depending onthe nature of the ring A,

[0023] heteroaryl being understood to mean any aromatic, mono- orbi-cyclic, 5- to 10-membered group containing from 1 to 3 hetero atomsselected from oxygen, nitrogen and sulphur,

[0024] the term “substituted” used in respect of the expressions“phenyl”, “naphthyl” or “heteroaryl” being understood to mean that thegroups concerned may be substituted by one or more groups, which may bethe same or different, selected from linear or branched (C₁-C₆)alkyl,linear or branched (C₁-C₆)alkoxy, mercapto, linear or branched(C₁-C₆)-alkylthio, amino, linear or branched (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino in which each alkyl moiety is linear or branched,linear or branched (C₁-C₆)polyhaloalkyl and hydroxy and halogen atoms,

[0025] it being understood that:

[0026] when R₂ and R₃ together form an oxo group and simultaneously R₅represents a hydrogen atom and R₆ represents a hydrogen atom or does notexist, then R₄ is other than a phenyl group substituted by one groupselected from hydroxy, alkoxy, CF₃ and halogen (except for bromine whenA represents a piperidine group), or by several groups selected fromhydroxy and alkoxy,

[0027] when R₂ represents a hydrogen atom and R₃ represents a hydroxygroup and simultaneously R₅ represents a hydrogen atom and R₆ representsa hydrogen atom or does not exist, then R₄ is other than a phenyl groupsubstituted by one group selected from hydroxy, linear or branched(C₁-C₆)alkoxy, linear or branched (C₁-C₆)alkyl and chlorine. or byseveral groups selected from hydroxy and alkoxy,

[0028] the compound of formula (I) may not represent1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)ethanol nor2-(2-pyridinyl)cyclohexanone,

[0029] their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.

[0030] Among the pharmaceutically acceptable acids there may bementioned, without implying any limitation, hydrochloric acid,hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid,trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinicacid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citricacid, ascorbic acid, methane-sulphonic acid, camphoric acid, oxalic acidetc.

[0031] Among the pharmaceutically acceptable bases there may bementioned, without implying any limitation, sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine etc.

[0032] Preferred compounds of the invention are compounds of formula (I)wherein the group

[0033] represents a pyridinyl group, an N-methylpyridinium group, apiperidinyl group or an N-methylpiperidinyl group.

[0034] Preferred substituents R₄ are a phenyl group or substitutedphenyl group, especially substituted by a halogen atom, preferably abromine atom.

[0035] Advantageously, the invention relates to compounds of formula (I)wherein R₅ represents a hydrogen atom or a group of formula (II).

[0036] Preferred groups R₂ and R₃ are those wherein R₂ and R₃ togetherform an oxo group or R₂ represents a hydrogen atom and R₃ represents ahydroxy group.

[0037] Even more advantageously, the invention relates to the compoundsof formula (I) which are:

[0038] 1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,

[0039] (R)-1-(4-bromophenyl)-2-(1 methyl-2-piperidinyl)-1-ethanone,

[0040] (S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone,

[0041] 1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,

[0042] (S,S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,

[0043] (R,R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol,

[0044] 1-methyl-2-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium iodide.

[0045] The enantiomers and diastereoisomers, as well as the additionsalts with a pharmaceutically acceptable acid or base, of the preferredcompounds of the invention form an integral part of the invention.

[0046] The invention relates also to a process for the preparation ofcompounds of formula (I), which process is characterised in that thereis used as starting material the compound of formula (III):

[0047] wherein X represents a hydrogen or fluorine atom, which isalkylated by means of an agent such as, for example, alkylpara-toluenesulphonate or alkyl trifluoromethanesulphonate to yield thecompound of formula (IV):

[0048] wherein X is as defined hereinbefore, R′₆ represents a linear orbranched (C₁-C₆)alkyl group and Y⁻ represents a para-toluenesulphonateor trifluoromethanesulphonate group for example,

[0049] which is reacted with one or two compounds, which may be the sameor different, of formula (V):

[0050] wherein R_(a) and R_(b), together with the nitrogen atom carryingthem, form a 5- or 6-membered heterocycle which may contain, in additionto the nitrogen atom, another hetero atom selected from sulphur, oxygenand nitrogen, and R_(c) represents a hydrogen atom or a group of formula(VI):

[0051] wherein R₄ and R₁ are as defined hereinbefore,

[0052] it being understood that at least one of the compounds of formula(V) contains a group of formula (VI),

[0053] to yield the compound of formula (I/a), a particular case of thecompounds of formula (I):

[0054] wherein R₁, R₄, R_(a), R_(b), R′₆ and Y⁻ are as definedhereinbefore and X′ represents a hydrogen atom, a group —NR′_(a)R′_(b)(wherein R′_(a) and R′_(b) may have any of the meanings of R_(a) andR_(b), respectively) or a group of formula (VII):

[0055] wherein R′_(a), R′_(b), R′₁ and R′₄ may have any of the meaningsof R_(a), R_(b), R₁ and R₄, respectively,

[0056] which compound of formula (I/a) may be subjected to halohydricacid such as HCl, HBr or HI, or to the action of ammonium salts such asNH₄ ⁺PF₆ ⁻ to yield a compound of formula (I/a′):

[0057] wherein R₁, R₄, R_(a), R_(b), R′₆ and X′ are as definedhereinbefore and Y′⁻ represents a halogen anion or a PF₆ ⁻ group,

[0058] which compound of formula (I/a′) may be hydrolysed using aconcentrated hydrochloric acid solution to yield the compound of formula(I/b), a particular case of the compounds of formula (I):

[0059] wherein R₁, R₄, R′₆ and Y′⁻ are as defined hereinbefore and X″represents a hydrogen atom, a group —NR′_(a)R′_(b) as definedhereinbefore or a group of formula (VIII):

[0060] wherein R′₁ and R′₄ may have any of the meanings of R₁ and R₄,respectively,

[0061] the compounds of formula (I/a), (I/a′) and (I/b) constituting thecompound of formula (I/c), a particular case of the compounds of formula(I):

[0062] wherein R₁, R₄ and R′₆ ⁻ are as defined hereinbefore, Y″⁻represents a group Y⁻ or Y′⁻ as defined hereinbefore, R_(2a) and R_(3a)together form an oxo group, or R_(2a) and R₁ form an additional bondand. in that case, R_(3a) represents a group NR′_(a)R′_(b) as definedhereinbefore, and X′″ represents a hydrogen atom, a group NR′_(a)R′_(b)or a group of formula (IX):

[0063] wherein R′₁, R′_(2a), R′_(3a) and R′₄ may have any of themeanings of R₁, R_(2a), R_(3a) and R₄, respectively,

[0064] which is converted into a corresponding iodinated salt by theaction of NaI to yield the compound of formula (I/d), a particular caseof the compounds of formula (I):

[0065] wherein R₁, R_(2a), R_(3a), R₄, R′₆ and X′″ are as definedhereinbefore,

[0066] which is

[0067] either subjected to catalytic hydrogenation, for example overplatinum oxide, to yield the compound of formula (I/e), a particularcase of the compounds of formula (I):

[0068] wherein R₁, R_(2a), R_(3a), R₄, X′″ and R′₆ are as definedhereinbefore,

[0069] or subjected to the action of a pyridinium salt to yield thecompound of formula (I/f), a particular case of the compounds of formula(I):

[0070] wherein R₁, R_(2a), R_(3a), R₄ and X′″ are as definedhereinbefore,

[0071] which may be hydrogenated by catalytic hydrogenation to yield thecompound of formula (I/g), a particular case of the compounds of formula(I):

[0072] wherein R₁, R_(2a), R_(3a), R₄ and X′″ are as definedhereinbefore,

[0073] it being possible for the compounds of formulae (I/b) and (I/c)to (I/g) wherein R_(2a) and R_(3a) together form an oxo group to besubjected to the action of a reducing agent such as, for example. NaBH₄to yield the compound of formula (I/h), a particular case of thecompounds of formula (I):

[0074] wherein A, R₁, R₄ and R₆ are as defined hereinbefore and X′″represents a hydrogen atom, a group NR′_(a)R′_(b) as definedhereinbefore or a group of formula (X):

[0075] wherein R′₁, R′₂, R′₃ and R′₄ are as defined hereinbefore,

[0076] which compound of formula (I/h) can be obtained as pureenantiomers from compounds of formula (I/b) and (I/c) to (I/g) whereinR_(2a) and R_(3a) together form an oxo group using an enantioselectivereduction catalyst such as (R,R)-(−) or(S,S)-(+)—N,N′-bis(3,5-di-tert-butylsalicylidene-1,2-cyclohexanediaminomanganese(III) chloride,

[0077] the compounds of formulae (I/a) to (I/h) constituting thetotality of the compounds of the invention, which may be purifiedaccording to a conventional separation technique, are converted, ifdesired, into their addition salts with a pharmaceutically acceptableacid or base and are separated, where appropriate, into their isomersaccording to a conventional separation technique.

[0078] In addition to the fact that the compounds of the presentinvention are new, they exhibit antalgic properties and propertiesfacilitating cognitive processes, rendering them of use in the treatmentof pain and of cognitive deficiencies associated with cerebral ageingand with neurodegenerative diseases, such as Alzheimer's disease,Parkinson's disease, Pick's disease, Korsakoffs disease and frontal lobeand subcortical dementias.

[0079] The invention relates also to pharmaceutical compositionscomprising as active ingredient at least one compound of formula (I)together with one or more appropriate, inert, non-toxic excipients.Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral (intravenous or subcutaneous) and nasal administration,tablets or dragees, sublingual tablets, gelatin capsules, lozenges.suppositories, creams, ointments, dermal gels, injectable preparations,drinkable suspensions etc.

[0080] The dosage used can be adapted to the nature and the severity ofthe disorder. the administration route and the age and weight of thepatient. The dosage varies from 0.01 mg to 1 g per day in one or moreadministrations.

[0081] The following Examples illustrate the invention but do not limitit in any way.

[0082] The following Preparations yield compounds of the invention orsynthesis intermediates that are useful in the preparation of compoundsof the invention.

[0083] Preparation 1: 2-Fluoro-1-methylpyridinium4-methylbenzenesulphonate

[0084] 10 mmol of 2-fluoropyridine and 10 mmol of methyl4-methylbenzenesulphonate are mixed in a 50 ml round-bottomed flask andstirred for 6 hours at 70° C. under a nitrogen atmosphere. The saltobtained in the form of a white solid is used without additionalpurification in the following step.

[0085] Preparation 2: 1-(1-Phenylvinyl)Pyrrolidine

[0086] 100 g of molecular sieve are heated at 500° C. for 8 hours andthen added to a mixture of 20 mmol of acetophenone and 22 mmol ofpyrrolidine in 200 ml of anhydrous ether The reaction mixture is stirredat ambient temperature until, in the infra-red, no more free ketone (C═O1689 cm⁻¹) is detected in the supernatant and the absorption for theenamine (C═C—N 1600 cm⁻¹) is at a maximum. The mixture is then filteredand the molecular sieve is washed with ether. The solvent is evaporatedoff under reduced pressure and the crude residue is purified bydistillation under reduced pressure.

[0087] Boiling point: 110° C./2 mm Hg

[0088] Preparations 3 to 11 are obtained by proceeding as in Preparation2.

[0089] Preparation 3: 4-(1-Phenylvinyl)Morpholine

[0090] Boiling point: 125° C./2 mm Hg

[0091] Preparation 4: 1-[1-(4-Methylphenyl)Vinyl]Pyrrolidine

[0092] Boiling point: 135° C./10 mm Hg

[0093] Preparation 5: 1-[1-(4-Methoxyphenyl)Vinyl]Pyrrolidine

[0094] Boiling point: 160° C./0.4 mm Hg

[0095] Preparation 6: 1-[1-(4-Chlorophenyl)Vinyl]Pyrrolidine

[0096] Boiling point: 125° C./10 mm Hg

[0097] Preparation 7: 1-[1-(4-Bromophenyl)Vinyl]Pyrrolidine

[0098] Boiling point: 160° C./0.3 mm Hg

[0099] Preparation 8: 1-[1-(4-Fluorophenyl)Vinyl]Pyrrolidine

[0100] Boiling point: 140° C./0.3 mm Hg

[0101] Preparation 9: 1-[1-(2-Bromophenyl)Vinyl]Pyrrolidine

[0102] Boiling point: 130° C./0.3 mm Hg

[0103] Preparation 10: 1-[1-(3-Bromophenyl)Vinyl]Pyrrolidine

[0104] Boiling point: 165° C./0.3 mm Hg

[0105] Preparation 11: 1-(1-Cyclohexen-1-yl)Pyrrolidine

[0106] 1 g of para-toluenesulphonic acid is added to a mixture of 20mmol of cyclohexanone and 22 mmol of pyrrolidine in 200 ml of drybenzene. The reaction mixture is stirred at reflux until, in theinfra-red, the ketone has disappeared, with the enamine concomitantlyappearing. The solvent is then evaporated off and the crude residue ispurified by distillation in vacuo.

[0107] Boiling point: 110° C./15 mm Hg

[0108] Preparation 12: 1-(1-Cyclohexen-1-yl)Morpholine

[0109] The procedure is as in Preparation 11, the benzene being replacedby toluene and the pyrrolidine by morpholine.

[0110] Boiling point: 140° C./15 mm Hg

[0111] Preparation 13: 2,6-Difluoro-1-methylpyridiniumTrifluoromethanesulphonate

[0112] 10 mmol of 2,6-difluoropyridine and 10 mmol oftrifluoromethanesulphonic acid are mixed in a 50 ml round-bottomed flaskand the mixture is stirred for 1 hour at ambient temperature under anitrogen atmosphere. The white solid obtained is used directly in thefollowing reaction without further purification.

[0113] Preparation 14: 1-{1-[4-(Dimethylamino)Phenyl]Vinyl}Pyrrolidine

[0114] The procedure is as in Preparation 2.

[0115] Preparation 15: 1-[1-(2-Fluorophenyl)Vinyl]Pyrrolidine

[0116] The procedure is as in Preparation 2.

[0117] Preparation 16: 1-{1-[4-(Methylthio)Phenyl]Vinyl}Pyrrolidine

[0118] The procedure is as in Preparation 2.

[0119] Preparation 17: 1-{1-[4-(Trifluoromethyl)Phenyl]Vinyl}Pyrrolidine

[0120] The procedure is as in Preparation 2.

[0121] Preparation 18:2-Fluoro-1-ethylpyridinium-4-methylbenzenesulfonate

[0122] Title product is obtained using the same procedure than inPreparation 1 replacing methyl-4-methylbenzenesulfonate byethyl-4-methylbenzenesulfonate.

EXAMPLE 1 1-Methyl-2-[2-(4-methylphenyl)-2-oxoethyl]PyridiniumHexafluorophosphate

[0123] 20 mmol of the compound obtained in Preparation 1 are dissolvedin 15 ml of anhydrous acetonitrile under a nitrogen atmosphere, and 22mmol of the compound obtained in Preparation 4, in 10 ml ofacetonitrile, are added dropwise at ambient temperature. The reactionmixture is stirred at 80° C. for 2 hours and the solution becomes red.The solvent is evaporated off in vacuo and the viscous red residue istaken up in 30 ml of concentrated hydrochloric acid and heated at refluxfor 3 hours. The dark brown solution obtained is cooled to ambienttemperature and then 22 mmol of ammonium hexafluorophosphate are added.The precipitate obtained is filtered off, washed with cold water andwith ethyl acetate, and then recrystallised from ethanol.

[0124] Melting point: 163-165° C.

[0125] Elementary Microanalysis: C H N % calculated: 47.05 3.95 3.92 %found: 47.18 3.88 3.81

EXAMPLE 2 1-Methyl-2-[2-(4-methylphenyl)-2-oxoethyl]Pyridinium Iodide

[0126] 10 mmol of the compound obtained in Example 1 are dissolved in 35ml of acetone, and 15 mmol of NaI are added in portions of 100 mg. Awhite precipitate is obtained immediately and the mixture is stirred for14 hours in a sealed tube at ambient temperature. The white solidobtained is filtered off and washed with acetone.

[0127] Melting point: 191-193° C.

[0128] Elementary Microanalysis: C H N % calculated: 49.56 4.16 4.13 %found: 49.82 4.12 4.40

[0129] The procedure in Examples 3 to 14 is as in Examples 1 and 2.

EXAMPLE 3 1-Methyl-2-(2-oxo-2-(4-methoxyphenyl)Ethyl)PyridiniumHexafluorophosphate

[0130] Starting Compounds: Preparations 1 and 5

[0131] Melting point: 168-170° C.

[0132] Elementary Microanalysis: C H N % calculated: 46.50 4.17 3.62 %found: 46.82 4.10 3.78

EXAMPLE 4 1-Methyl-2-[2-oxo-2-(4-methoxyphenyl)Ethyl]Pyridinium Iodide

[0133] Starting Compound: Example 3

[0134] Melting point: 214-216° C.

[0135] Elementary Microanalysis C H N % calculated: 47.78 4.37 3.79 %found: 48.67 4.68 4.02

EXAMPLE 5 1-Methyl-2-[2-oxo-2-(4-chlorophenyl)ethyl]PyridiniumHexafluorophosphate

[0136] Starting Compounds: Preparations 1 and 6

[0137] Melting point. 152-154° C.

[0138] Elementary Microanalysis:. C H N % calculated: 42.96 3.35 3.58 %found: 42.80 3.20 3.18

EXAMPLE 6 1-Methyl-2-[2-oxo-2-(4-chlorophenyl)Ethyl]Pyridinium Iodide

[0139] Starting compound: Example 5

[0140] Melting point. 212-214° C.

[0141] Elementary Microanalysis: C H N % calculated: 45.04 3.51 3.75 %found: 45.50 3.65 3.88

EXAMPLE 7 1-Methyl-2-[2-oxo-2-(4-bromophenyl)Ethyl]PyridiniumHexafluorophosphate

[0142] Starting Compounds: Preparations 1 and 7

[0143] Melting point: 185-187° C.

[0144] Elementary Microanalysis: C H N % calculated: 38.62 3.01 3.22 %found: 38.43 3.10 3.54

EXAMPLE 8 1-Methyl-2-[2-oxo-2-(4-bromophenyl)Ethyl]Pyridinium Iodide

[0145] Starting compound: Example 7

[0146] Melting point. 222-224° C.

[0147] Elementary Microanalysis:. C H N % calculated: 40.30 3.14 3.36 %found: 40.46 3.30 3.26

EXAMPLE 9 1-Methyl-2-(2-oxocyclohexyl)Pyridinium Hexafluorophosphate

[0148] Starting Compounds: Preparations 1 and 11 or 12

[0149] Elementary Microanalysis: C H N % calculated: 42.97 4.81 4.18 %found: 43.21 4.76 4.01

EXAMPLE 10 1-Methyl-2-(2-oxocyclohexyl)Pyridinium Iodide

[0150] Starting Compound: Example 9

[0151] Melting point: 151-153° C.

[0152] Elementary Microanalysis C H N % calculated: 45.42 5.09 4.42 %found: 45.76 4.96 4.66

EXAMPLE 11 1-Methyl-2-[2-oxo-2-(3-bromophenyl)Ethyl]PyridiniumHexafluorophosphate

[0153] Starting compounds: Preparations 1 and 10

EXAMPLE 12 1-Methyl-2-[2-oxo-2-(3-bromophenyl)Ethyl]Pyridinium IodideStarting Compound: Example 11

[0154] Melting point: 217-218° C.

[0155] Elementary Microanalysis: C H N % calculated: 40.30 3.14 3.36 %found: 40.20 3.25 2.90

EXAMPLE 13 1-Methyl-2-[2-oxo-2-(2-bromophenyl)Ethyl]PyridiniumHexafluorophosphate

[0156] Starting compounds: Preparations 1 and 9

EXAMPLE 14 1-Methyl-2-[2-oxo-2-(2-bromophenyl)Ethyl]Pyridinium Iodide

[0157] Starting Compound: Example 13

[0158] Melting point: 204-205° C.

[0159] Elementary Microanalysis C H N % calculated: 40.30 3.14 3.36 %found: 40.26 3.32 3.04

EXAMPLE 15a 1-Methyl-2-[2-oxo-(2-fluorophenyl)Ethyl]Pyridinium Iodide

[0160] The procedure is as in Examples 1 and 2, starting from thecompound obtained in Preparation 15.

EXAMPLE 15b 1-(2-Fluorophenyl)-2-(1-methyl-2-piperidinyl)EthanoneHydriodide

[0161] 3 mmol of the compound obtained in Example 15a are dissolved in150 ml of ethanol, and 50 mg of platinum oxide are added all at once.Hydrogenation is carried out at an initial pressure of 5 atm at 24° C.When the calculated theoretical volume of hydrogen has been absorbed(after approximately 3 hours), the catalyst is filtered off and washedwith ethanol. The solvent is evaporated off and the residue obtained isrecrystallised.

[0162] Melting point: 118-119° C.

[0163] Examples 16 to 21 are obtained by proceeding as in Example 15b.

EXAMPLE 16 2-(1-Methyl-2-piperidinyl)-1-(4-methoxyphenyl)-1-ethanoneHydriodide

[0164] Starting compound: Example 4

[0165] Melting point: 201-203° C.

[0166] Elementary Microanalysis: C H N % calculated: 47.99 5.91 3.73 %found: 48.10 6.01 3.45

EXAMPLE 17 2-(1-Methyl-2-piperidinyl)-1-(4-chlorophenyl)-1-ethanoneHydriodide

[0167] Starting Compound: Example 6

[0168] Melting point: 158-160° C.

[0169] Elementary Microanalysis: C H N % calculated: 44.32 5.05 3.69 %found: 44.46 5.32 3.68

EXAMPLE 18 2-(1-Methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanoneHydriodide

[0170] Starting Compound: Example 8

[0171] Melting point: 182-184° C.

[0172] Elementary Microanalysis: C H N % calculated: 39.72 4.53 3.31 %found: 39.81 4.60 3.54

EXAMPLE 18a (R)-2-(1-Methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanoneHydrochloride

[0173] A solution of oxalyl chloride (5 mmol) in dry CH₂Cl₂ (10 ml) wasplaced in an oven-dried 25 ml flask which was degassed and filled withnitrogen. DMSO (10 mmol) was added dropwise through a syringe at −50 to−60° C. The reaction mixture was stirred for minutes. A solution ofcompound of Example 60 (2) (0,5 mmol) in CH₂Cl₂ (5 ml) was then addeddropwise within 5 minutes and stirring was continued for another 30minutes. Triethylamine (30 mmol) was added and the solution was stirredfor 10 minutes and then allowed to warm to room temperature. Water wasthen added to the reaction mixture and the aqueous solution wasextracted with CH₂Cl₂. The combined organic phases was dried (MgSO₄) andconcentrated. The residue was purified by flash column chromatography(silica gel, AcOEt-MeOH—NH₄OH) affording an unstable light yellow oilwhich was immediately dissolved in an HCl-ether solution forming a whitesolid. Recrystallisation of this solid from MeOH-ether produced puretitle product.

[0174] Melting point: 191-194° C.

[0175] [α]=+10(c=0.1; MeOH)

EXAMPLE 18b (S)-2-(1-Methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanoneHydrochloride

[0176] The title product is obtained using the same procedure than inExample 18a starting from compound of Example 60 (1).

[0177] Melting point. 192-194° C.

[0178] [α]=−9(c=0.1; MeOH)

EXAMPLE 19 2-(1-Methyl-2-piperidinyl)Cyclohexanone Hydriodide

[0179] Starting Compound: Example 10

[0180] Melting point: 160-162° C.

EXAMPLE 20 2-(1-Methyl-2-piperidinyl)-1-(3-bromophenyl)-1-ethanoneHydriodide

[0181] Starting Compound: Example 12

[0182] Melting point: 134-136° C.

[0183] Elementary Microanalysis: C H N % calculated: 39.72 4.53 3.31 %found: 39.88 4.45 3.26

EXAMPLE 21 2-(1-Methyl-2-piperidinyl)-1-(2-bromophenyl)-1-ethanoneHydriodide

[0184] Starting compound: Example 14

[0185] Melting point: 163.5-164° C.

[0186] Elementary Microanalysis: C H N % calculated: 39.72 4.53 3.31 %found: 39.66 4.47 3.26

EXAMPLE 22 1-Methyl-2-[2-phenyl-2-(1-pyrrolidinyl)Ethenyl]PyridiniumHexafluorophosphate

[0187] 20 mmol of the compound obtained in Preparation 1 are dissolvedin 15 ml of dry acetonitrile under a nitrogen atmosphere. A solution of22 mmol of the compound obtained in Preparation 2 in 10 ml ofacetonitrile is added dropwise, with stirring, at ambient temperature.The reaction mixture is stirred for 14 hours at ambient temperature andthen for 2 hours at 80° C. The solution becomes red. The solvent isevaporated off under reduced pressure, and 30 ml of cold water and then22 mmol of ammonium hexafluorophosphate in 20 ml of ethyl acetate/ether(1/1) are added to the viscous red residue obtained. After filtrationand washing with water and then with AcOEt/Et₂O (1/1), the pure titleproduct is obtained.

[0188] Melting point: 143-145° C.

[0189] Elementary Microanalysis: C H N % calculated: 52.67 5.16 7.83 %found: 52.97 5.26 7.81

EXAMPLE 23 1-Methyl-2-[2-phenyl-2-(1-pyrrolidinyl)Ethenyl]PyridiniumIodide

[0190] The same procedure is used as in Example 2.

[0191] Melting point: 200-202° C.

EXAMPLE 24 1-Methyl-2-[2-(4-morpholinyl)-2-Phenylethenyl]PyridiniumHexafluorophosphate

[0192] The same procedure is used as in Example 22.

[0193] Starting Compounds: Preparations 1 and 3

[0194] Melting point 168-170° C.

[0195] Elementary Microanalysis: C H N % calculated: 50.71 4.96 6.57 %found: 50.68 4.88 6.44

EXAMPLE 25 1-Methyl-2-[2-(4-morpholinyl)-2-Phenylethenyl]PyridiniumIodide

[0196] The procedure is as in Example 2.

EXAMPLE 261-Methyl-2-(4-morpholinyl)-6-[2-(4-morpholinyl)-2-phenylethenyl]-pyridiniumHexafluorophosphate

[0197] 20 mmol of the compound obtained in Preparation 13 are dissolvedin 15 ml of dry acetonitrile under a nitrogen atmosphere. 22 mmol ofmorpholine and 22 mmol of the compound obtained in Preparation 3 areadded and the mixture is stirred for 14 hours at ambient temperature andthen for 2 hours at 80° C. The procedure is then as in Example 22.

EXAMPLE 271-Methyl-2-(4-morpholinyl)-6-[2-(4-morpholinyl)-2-phenylethenyl]-pyridiniumIodide

[0198] The procedure is as in Example 2.

[0199] Melting point 214-216° C.

EXAMPLE 28 1-Methyl-2,6-bis(2-oxo-2-phenylethyl)PyridiniumTrifluoromethanesulphonate

[0200] 20 mmol of the compound obtained in Preparation 13 are dissolvedin 15 ml of dry acetonitrile. A solution, in 15 ml of acetonitrile, of44 mmol of the compound obtained in Preparation 2 is added dropwise at0° C., with stirring, under a nitrogen atmosphere. The reaction mixtureis then stirred for 14 hours at ambient temperature. The solutionbecomes red; the solvent is then evaporated off and the viscous redresidue obtained is taken up in 50 ml of concentrated hydrochloric acidand heated at reflux for 3 hours. After cooling to ambient temperature,the title compound crystallises out in the form of white needles, whichare filtered off and then washed with cold water and with ethyl acetate.

[0201] Melting point: 175° C.

[0202] Elementary Microanalysis: C H N % calculated: 57.61 4.61 2.92 %found: 57.82 4.40 2.99

EXAMPLE 29 1-Methyl-2,6-bis(2-oxo-2-phenylethyl)Pyridinium Iodide

[0203] The procedure is as in Example 2.

[0204] Melting point: 197-199° C.

[0205] Elementary Microanalysis: C H N % calculated: 57.76 4.41 3.06 %found: 57.88 4.52 3.35

EXAMPLE 30 2,6-Bis [2-(4-bromophenyl)-2-oxoethyl]-1-methylpyridiniumTrifluoromethanesulphonate

[0206] The procedure is as in Example 28.

[0207] Starting compounds: Preparations 13 and 7

EXAMPLE 31 2,6-Bis [2-(4-bromophenyl)-2-oxoethyl]-1-methylpyridiniumIodide

[0208] The procedure is as in Example 2.

EXAMPLE 32 1-Methyl-2,6-bis(2-oxocyclohexyl)PyridiniumHexafluorophosphate

[0209] 20 mmol of the compound obtained in Preparation 13 are dissolvedin 15 ml of acetonitrile, and 44 mmol of the compound obtained inPreparation 11, dissolved in 15 ml of acetone, are added at 0° C. undera nitrogen atmosphere. The reaction mixture is returned to ambienttemperature and stirred for 3 hours at 80° C. The solution becomes redand, after the solvent has been evaporated off under reduced pressure,the residue is taken up in 50 ml of concentrated hydrochloric acid andheated at reflux for 3 hours. After cooling, the solution is filtered toremove any solid impurities and 22 mmol of NH₄PF₆ are added. Afterextraction with ethyl acetate and drying over MgSO₄, the solvent isevaporated off under reduced pressure and the solid obtained isrecrystallised from an ethanol/ethyl acetate mixture.

[0210] Elementary Microanalysis: C H N % calculated: 50.10 5.61 3.25 %found: 50.28 5.31 3.66

EXAMPLE 33 1-Methyl-2,6-bis(2-oxocyclohexyl)Pyridinium Iodide

[0211] The procedure is as in Example 2.

EXAMPLE 341-Methyl-2-[2-(4-methylphenyl)-2-oxoethyl]-6-(2-oxo-2-phenylethyl)-pyridiniumTrifluoromethanesulphonate

[0212] 20 mmol of the compound obtained in Preparation 13 are dissolvedin 15 ml of dry acetonitrile, and then 22 mmol of the compound obtainedin Preparation 2, in 10 ml of acetonitrile, are added dropwise at 0° C.under a nitrogen atmosphere. The reaction mixture is then returned toambient temperature and stirred for 3 hours at that temperature. 22 mmolof the compound obtained in Preparation 4, in 10 ml of acetonitrile, arethen added and the reaction mixture is stirred for a further 14 hours.The solvent is then evaporated off and the viscous red residue obtainedis taken up in 50 ml of concentrated hydrochloric acid and heated atreflux for 3 hours. After cooling, the title compound crystallises outin the form of white needles, which are filtered off and washed insuccession with water and ethyl acetate.

[0213] Melting point: 188-190° C.

[0214] Elementary Microanalysis: C H N % calculated: 58.40 4.50 2.84 %found: 58.54 4.76 2.78

EXAMPLE 351-Methyl-2-[2-(4-methylphenyl)-2-oxoethyl]-6-(2-oxo-2-phenylethyl)-pyridiniumIodide

[0215] The procedure is as in Example 2.

[0216] Melting point: 205-206° C.

[0217] Elementary Microanalysis: C H N % calculated: 58.59 4.71 2.91 %found: 58.65 4.65 2.76

[0218] Examples 36 to 49 are obtained by proceeding as in Examples 34and 35.

EXAMPLE 362-[2-(4-Chlorophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumTrifluoromethanesulphonate

[0219] Starting Compounds: Preparations 13, 2 and 6

[0220] Melting point. 199-201° C.

EXAMPLE 372-[2-(4-Chlorophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumIodide

[0221] Starting Compound: Example 36

[0222] Melting point: 213-215° C.

EXAMPLE 382-[2-(4-Fluorophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumTrifluoromethanesulphonate

[0223] Starting Compounds: Preparations 13, 2 and 8

[0224] EXAMPLE 39

2-[2-(4-Fluorophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumIodide

[0225] Starting Compound: Example 38

[0226] Melting point: 220-222° C.

EXAMPLE 402-[2-(4-Bromophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumTrifluoromethanesulphonate

[0227] Starting Compounds: Preparations 13, 2 and 7

EXAMPLE 412-[2-(4-Bromophenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumIodide

[0228] Starting compound: Example 40

[0229] Melting point: 218-220° C.

EXAMPLE 422-[2-(4-Bromophenyl)-2-oxoethyl]-6-[2-(4-chlorophenyl)-2-oxoethyl]-1-methylpyridiniumTrifluoromethanesulphonate

[0230] Starting Compounds: Preparations 13, 6 and 7

[0231] Melting point: 226-228° C.

EXAMPLE 432-[2-(4-Bromophenyl)-2-oxoethyl]-6-[2-(4-chlorophenyl)-2-oxoethyl]-1-methylpyridiniumIodide

[0232] Starting Compound: Example 42

[0233] Melting point: 226-227° C.

EXAMPLE 442-[2-(4-Methoxyphenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumTrifluoromethanesulphonate

[0234] Starting Compounds: Preparations 13, 2 and 5

[0235] Melting point: 193-195° C.

EXAMPLE 452-[2-(4-Methoxyphenyl)-2-oxoethyl]-1-methyl-6-(2-oxo-2-phenylethyl)-pyridiniumIodide

[0236] Starting Compound: Example 44

[0237] Melting point: 203-205° C.

EXAMPLE 462-[2-(4-Fluorophenyl)-2-oxoethyl]-6-[2-(4-methoxyphenyl)-2-oxoethyl]-1-methylpyridiniumTrifluoromethanesulphonate

[0238] Starting Compounds: Preparations 13, 5 and 8

[0239] Melting point: 208-210° C.

EXAMPLE 472-[2-(4-Fluorophenyl)-2-oxoethyl]-6-[2-(4-methoxyphenyl)-2-oxoethyl]-1-methylpyridiniumIodide

[0240] Starting Compound: Example 46

[0241] Melting point: 219-220° C.

EXAMPLE 482-[2-(4-Methoxyphenyl)-2-oxoethyl]-1-methyl-6-[2-(4-methylphenyl)-2-oxoethyl]pyridiniumTrifluoromethanesulphonate

[0242] Starting Compounds: Preparations 13, 4 and 5

EXAMPLE 492-[2-(4-Methoxyphenyl)-2-oxoethyl]-1-methyl-6-[2-(4-methylphenyl)-2-oxoethyl]PyridiniumIodide

[0243] Starting Compound: Example 48

EXAMPLE 501-(4-Methoxyphenyl)-2-{1-methyl-6-[2-(4-methylphenyl)-2-oxoethyl]-2-piperidinyl}-1-ethanoneHydriodide

[0244] 3 mmol of the compound obtained in Example 49 are dissolved in150 ml of ethanol and then 70 mg of platinum oxide are added all atonce. Hydrogenation is carried out using an initial pressure of 3atmospheres at 24° C. When the theoretical volume of hydrogen has beenabsorbed (after approximately 3 hours), the catalyst is filtered off andwashed with ethanol. The solvent is then evaporated off and the titleproduct is obtained in the form of a white solid.

[0245] Examples 51 to 56 are obtained by proceeding as in Example 50.

EXAMPLE 512-{1-Methyl-6-[2-(4-methylphenyl)-2-oxoethyl]-2-piperidinyl}-1-phenyl-1-ethanoneHydriodide

[0246] Starting compound: Example 35

[0247] Melting point: 192-193° C.

EXAMPLE 521-(4-Chlorophenyl)-2-[1-methyl-6-(2-oxo-2-phenylethyl)-2-piperidinyl]-1-ethanoneHydriodide

[0248] Starting Compound: Example 37

[0249] Melting point: 152-154° C.

EXAMPLE 531-(4-Fluorophenyl)-2-[1-methyl-6-(2-oxo-2-phenylethyl)-2-piperidinyl]-1-ethanoneHydriodide

[0250] Starting Compound: Example 39

[0251] Melting point: 152-154° C.

EXAMPLE 541-(4-Bromophenyl)-2-{6-[2-(4-chlorophenyl)-2-oxoethyl]-1-methyl-2-piperidinyl}-1-ethanoneHydriodide

[0252] Starting Compound: Example 43

[0253] Melting point: 200-202° C.

EXAMPLE 551-(4-Bromophenyl)-2-[1-methyl-6-(2-oxo-2-phenylethyl)-2-piperidinyl]-1-ethanoneHydriodide

[0254] Starting Compound: Example 41

EXAMPLE 561-(4-Bromophenyl)-2-{6-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl-2-piperidinyl}-1-ethanoneHydriodide

[0255] Starting Compound: Example 31

EXAMPLE 57a2-{2-[4-(Dimethylamino)phenyl]-2-oxoethyl}-1-methylpyridinium Iodide

[0256] The procedure is as in Examples 1 and 2, starting from thecompound obtained in Preparation 14.

EXAMPLE 57b 1-[4-(Dimethylamino)phenyl]-2-(2-pyridinyl)Ethanone

[0257] 8 mmol of the compound obtained in Example 57a are added to 15 gof boiling pyridine hydrochloride and the dark solution obtained isheated at reflux for 10 minutes. The hot reaction mixture is poured onto30 g of ice and 20 ml of ammonium hydroxide 37%. After cooling in an icebath for approximately 2 hours, the title compound crystallises out andthe crystals are filtered off and washed with cold water.

EXAMPLE 58 1-(4-Bromophenyl)-2-(2-pyridinyl)-1-ethanol

[0258] Step A: 1-(4-Bromophenyl)-2-(2-pyridinyl)-1-ethanone

[0259] 8 mmol of the compound obtained in Example 8 are added to 15 g ofboiling pyridine hydrochloride and the dark solution obtained is heatedat reflux for 10 minutes. The hot reaction mixture is poured onto 30 gof ice and 20 ml of ammonium hydroxide 37%. After cooling in an ice bathfor approximately 2 hours, the title compound crystallises out in theform of yellow-green crystals, which are filtered off and washed withcold water.

[0260] Step B: 1-(4-Bromophenyl)-2-(2-pyridinyl)-1-ethanol

[0261] 1 mmol of the compound obtained in Step A is dissolved in 15 mlof ethanol, and 1.5 mmol of NaBH₄ are added in two portions. Thereaction mixture is stirred for 3 hours; the reaction is then quenchedusing 0.5 ml of acetic acid; the mixture is rendered basic with 10%NaOH, and extracted with dichloromethane (3×15 ml). The organic phase isdried over MgSO₄, evaporated and the solid obtained is recrystallisedfrom ethanol.

EXAMPLE 58a S-(−)-1-(4-Bromophenyl)-2-(2-pyridinyl)-1-ethanol

[0262] A solution of NaBH₄ (1,51 g, 40 mmol) modified with ethanol (2.34ml) and tetrahydrofurfuryl alcohol (20 ml) in CHCl₃ (40 ml) was addeddropwise to a solution of the compound obtained in step A of Example 58(8.28 g, 30 mmol) and (R,R)-(−)-Jacobsen's MnCl catalyst (420 mg) inCHCl₃ (30 ml) at −20° C. under a nitrogen atmosphere. The reaction wasmonitored by TLC and quenched by addition of sat. NH₄Cl solution (15 ml)on completion. The aqueous solution was extracted with CH₂Cl₂ and theextract dried and evaporated. The residue was purified by columnchromatography (silica gel. ethyl acetate-petroleum ether) to affordtitle product.

[0263] Melting point: 161-162° C.

[0264] [α]=−34 (c=1, CHCl₃)

[0265] Elementary Microanalysis: C H N % calculated: 56.14 4.35 5.04 %found: 56.25 4.06 4.99

EXAMPLE 58b R-(+)-1-(4-Bromophenyl)-2-(2-pyridinyl)-1-ethanol

[0266] Title product is obtained using the same process than in Example58a with (S,S)-(+)-Jacobsen's MnCl catalyst.

[0267] Melting point: 161-162.5° C.

[0268] [α]=+34 (c=1, CHCl₃)

[0269] Elementary Microanalysis: C H N % calculated: 56.14 4.35 5.04 %found: 56.25 4.06 4.99

EXAMPLE 59 1-(4-Bromophenyl)-2-(2-piperidinyl)-1-ethanol

[0270] 1 mmol of the compound obtained in Example 58 is dissolved in 20ml of acetic acid, and 8 mg of platinum oxide are added. Thehydrogenation is carried out starting from an initial pressure of 3atmospheres at 24° C. After reacting for 3 hours, the catalyst isfiltered off and washed with dichloromethane. The solvents areevaporated off and the residue obtained is dissolved in 10% sodiumhydroxide solution and extracted with dichloromethane. The organic phaseis washed with water, dried over MgSO₄ and then evaporated off to yieldthe title compound in the form of a white solid.

EXAMPLE 60 1-(4-Bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol

[0271] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 18.

EXAMPLE 60(1)(S,S)-(−)-1-(4-Bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol

[0272] To compound obtained in Example 58a (1 mmol) in acetic acid (20ml) was added platinum oxide (20 mg) and the solution hydrogenated at 5atm. and 20° C. Removal of the catalyst and then the solvent, followedby addition of dichloromethane and aqueous sodium carbonate, washing anddrying of the organic layer, followed by evaporation, gave a mixture oftwo diastereoisomers of (S,S)-(−)-4′-bromo-norsedamine and(R,S)-(−)4′-bromo-norallosedamine. Recrystallisation from ethylacetate/petroleum ether (1:1) gave the pure S,S-isomer of1-(4-bromophenyl)-2-(2-piperidinyl)ethanol which was dissolved inacetonitrile (25 ml) and aqueous formaldehyde (37%, 25 ml). Then sodiumcyano-borohydride (0.312 g, 5 mmol) was added. The mixture was stirredat ambient for 1 hour and acetic acid added. After 20 minutes thesolution was neutralised with aqueous sodium hydroxide, extracted withdichloromethane, the extract dried and evaporated and the residuepurified by silica gel chromatography to give the title product(recrystallised from ethyl acetate-petroleum ether 1:1).

[0273] Melting point: 102-104° C.

[0274] [α]=−28 (c=1, EtOH)

[0275] Elementary Microanalysis: C H N % calculated: 56.38 6.76 4.70 %found: 56.72 6.66 5.01

EXAMPLE 60(2)(R,R)-(+)-1-(4-Bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol

[0276] Title product is obtained using the same procedure than inExample 60 (1) starting from compound obtained in Example 58b.

Melting point 102-104° C.

[0277] [α]=+28 (c=1, EtOH)

[0278] Elementary Microanalysis: C H N % calculated: 56.38 6.76 4.70 %found: 56.81 6.82 4.76

EXAMPLE 61a 2-{2-[4-(Methylthio)phenyl]-2-oxoethyl}-1-methylpyridiniumIodide

[0279] The procedure is as in Examples 1 and 2, starting from thecompound obtained in Preparation 16.

EXAMPLE 61b 1-[4-(Methylthio)phenyl]-2-(2-pyridinyl)Ethanone

[0280] The procedure is as in Example 57b, starting from the compoundobtained in Example 61a.

[0281] Melting point: 118-119.5° C.

EXAMPLE 62 1-Methyl-2-[2-(4-chlorophenyl)-2-hydroxyethyl]PyridiniumIodide

[0282] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 6.

[0283] Melting point: 172-173.5° C.

EXAMPLE 631-Methyl-2-{2-hydroxy-2-[4-(methylthio)Phenyl]Ethyl}Pyridinium Iodide

[0284] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 61a.

[0285] Melting point: 145-148° C.

EXAMPLE 64 2-{2-[4-(Dimethylamino)phenyl]-2-hydroxyethyl}PyridiniumIodide

[0286] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 57a.

Example 65 1-[4-(Methylthio)Phenyl]-2-(2-pyridinyl)Ethanol

[0287] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 61b.

EXAMPLE 66a1-Methyl-2-{2-oxo-2-[4-(trifluoromethyl)Phenyl]Ethyl}Pyridinium Iodide

[0288] The procedure is as in Examples 1 and 2, starting from thecompound obtained in Preparation 17.

EXAMPLE 66b 2-(2-Pyridinyl)-1-[4-(trifluoromethyl)Phenyl]Ethanol

[0289] Step A: 2-(2-Pyridinyl)-1-[4-(trifluoromethyl)phenyl]ethanone

[0290] The procedure is as in Example 57b, starting from the compoundobtained in Example 66a.

[0291] Step B: 2-(2-Pyridinyl)-1-[4-(trifluoromethyl)phenyl]ethanol

[0292] Starting from the compound obtained in Step A, the procedure isas in Step B of Example 58.

[0293] Melting point: 156-158° C.

EXAMPLE 67 1-(2-Fluorophenyl)-2-(2-pyridinyl)Ethanol

[0294] The procedure is as in Example 66b, starting from the compoundobtained in Example 15a.

[0295] Melting point: 71-73° C.

EXAMPLE 68 1-(3-Bromophenyl)-2-(2-pyridinyl)Ethanol

[0296] The procedure is as in Example 66b, starting from the compoundobtained in Example 12.

[0297] Melting point: 82-84° C.

EXAMPLE 69 1-(2-Bromophenyl)-2-(2-pyridinyl)Ethanol

[0298] The procedure is as in Example 66b, starting from the compoundobtained in Example 14. Oil.

EXAMPLE 70 2-(2-Piperidinyl)-1-[4-(trifluoromethyl)Phenyl]Ethanol

[0299] The procedure is as in Example 59, starting from the compoundobtained in Example 66b.

[0300] Melting point: 95-98° C.

EXAMPLE 71 1-(4-Chlorophenyl)-2-(1-methyl-2-piperidinyl)Ethanol

[0301] The procedure is as in Step B of Example 58, starting from thecompound obtained in Example 17.

[0302] Melting point: 84-87° C.

EXAMPLE 722-(1-Methyl-2-piperidinyl)-1-[4-(trifluoromethyl)Phenyl]Ethanol

[0303] The procedure is as in Step B of Example 58, starting from thecompound obtained in Step A of Example 66b.

EXAMPLE 73 2-[2-(4-Bromophenyl)-2-oxoethyl]-1-ethylpyridinium Chloride

[0304] Title product is obtained using the same procedure than inExample 1 starting from Preparations 1 and 7 without addition ofammonium hexafluorophosphate.

[0305] Melting point: 112-114° C.

EXAMPLE 74 2-[2-(4-Bromophenyl)-2-hydroxyethyl]-1-methylpyridiniumChloride

[0306] Title product is obtained using the same procedure than in step Bof Example 58 starting from the compound of Example 8.

[0307] Melting point 64-65° C.

Pharmacological Study of the Compounds of the Invention EXAMPLE A AcuteToxicity Study

[0308] The acute toxicity was evaluated after oral administration togroups each comprising 8 mice (26±2 grams). The animals were observed atregular intervals during the course of the first day, and daily for thetwo weeks following treatment. The LD₅₀ (dose that causes the death of50% of the animals) was evaluated and demonstrated the low toxicity ofthe compounds of the invention.

EXAMPLE B Abdominal Contractions Induced by Phenyl-p-benzoquinone (PBQ)in the NMRI Mouse

[0309] Intraperitoneal administration of an alcoholic solution of PBQcauses abdominal cramps in the mouse (SIEGMUND et al, Proc. Soc. Exp.Biol., 1957, 95, 729-731). The cramps are characterised by repeatedcontractions of the abdominal musculature, accompanied by extension ofthe hind limbs. Most analgesics antagonise these abdominal cramps(COLLIER et al., Brit. J. Pharmacol. Chem., 1968, 32 295-310). At t=0min., the animals are weighed and the compound being studied isadministered by the IP route. A group of control animals is given thesolvent used for the compound. At t=30 min., an alcoholic solution ofPBQ (0.2%) is administered by the IP route in a volume of 0.25 ml/mouse.Immediately after administration of the PBQ, the animals are placed incylinders of plexiglass (L=19.5 cm; I.D.=5 cm). From t=35 min. to t=45min., the animals' reaction is observed and the experimenter notes thetotal number of abdominal cramps per animal. The results are expressedas the percentage inhibition of the number of abdominal cramps measuredin the control animals, at the active dose of the compound studied.

[0310] The results obtained show a percentage inhibition ranging from 30to 90% for low active doses, which attests the antalgic properties ofthe compounds of the invention.

EXAMPLE C Social Recognition in the Wistar Rat

[0311] Initially described in 1982 by THOR and HOLLOWAY, (J. Comp.Physiol., 1982, 96, 1000-1006), the social recognition test hassubsequently been proposed by various authors (DANTZER et al.,Psychopharmacology, 1987, 91, 363-368; PERIO et al., Psychopharmacology,1989, 97, 262-268) for studying the mnemocognitive effects of newcompounds. The test is based on the natural expression of the olfactorymemory of the rat and its natural tendency to forget and allowsevaluation of memorisation, by recognition of a young congeneric animal,by an adult rat. A young rat (21 days), taken at random, is placed for 5minutes in the cage housing an adult rat. With the aid of a videodevice, the experimenter observes the social recognition behaviour ofthe adult rat and measures its overall duration. The young rat is thenremoved from the adult rat's cage and is placed in its own cage untilthe second introduction. The adult rat is given the compound under testand, after 2 hours, is again brought into the presence (5 minutes) ofthe young rat. The social recognition behaviour is then observed againand its duration measured. The assessment criterion is the difference(T₂-T₁), expressed in seconds, between the “recognition” times of the 2encounters.

[0312] The results obtained show a difference (T₂-T₁) ranging from −20 sto −45 s for doses ranging from 0.3 to 3 mg/kg, which shows that thecompounds of the invention very greatly enhance memorisation, even at alow dose.

EXAMPLE D Object Recognition in the Wistar Rat

[0313] The object recognition test in the Wistar rat was initiallydeveloped by ENNACEUR and DELACOUR (Behav. Brain Res., 1988, 31, 47-59).The test is based on the spontaneous exploratory activity of the animaland has the characteristics of episodic memory in humans. This memorytest is sensitive to ageing (SCALI et al., Eur. J. Pharmacol., 1997,325, 173-180) and to cholinergic dysfunctions (BARTOLINI et al., Pharm.Biochem. Behav. 1996, 53(2), 277-283) and is based on the differences inthe exploration of 2 objects of fairly similar shape—one familiar, theother new. Prior to the test, the animals are habituated to theenvironment (an enclosure without an object). In the course of a firstsession, the rats are placed (3 minutes) in the enclosure, in whichthere are 2 identical objects. The duration of exploration is measuredfor each object. In the course of the second session (3 minutes), 24hours later, 1 of the 2 objects is replaced by a new object. Theduration of exploration is measured for each object. The assessmentcriterion is the difference, Delta, expressed in seconds, between theexploration times for the new object and for the familiar object in thecourse of the second session. The control animals, previously treatedwith the carrier by the IP route 30 minutes before each session, explorethe familiar object and the new object in an identical manner, whichindicates that the object introduced earlier has been forgotten. Animalstreated with a compound that facilitates mnemocognition preferentiallyexplore the new object, which indicates that the object introducedearlier has been remembered.

[0314] The results obtained show a difference, Delta, ranging from 5 sto 10 s, for doses ranging from 0.03 to 3 mg/kg, which shows that thecompounds of the invention greatly enhance memorisation, even at a verylow dose.

EXAMPLE E Pharmaceutical Composition

[0315] Formulation for the preparation of 1000 tablets each comprising10 mg of active ingredient:

[0316] 2-(1-Methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanonehydriodide (Example 18) 10 g

[0317] Hydroxypropyl cellulose 2 g

[0318] Wheat starch 10 g

[0319] Lactose 100 g

[0320] Magnesium stearate 3 g

[0321] Talc 3 g

We claim:
 1. A compound of formula (I):

wherein: A represents pyridine, pyridinium or piperidine, R₂ representshydrogen and R₃ represents hydroxy, or R₂ and R₃ together form oxo, R₄represents unsubstituted or substituted phenyl, unsubstituted orsubstituted naphthyl or unsubstituted or substituted heteroaryl, R₁represents hydrogen, or R₁ and R₄, together with the two carbon carryingthem, form a ring containing 6 carbon, or R₁ and R₂ form an additionalbond and, in that case, R₃ represents a 5- or 6-membered heterocyclethat contains nitrogen atom by which it is bound and that may containanother hetero atom selected from sulphur, oxygen and nitrogen, R₅represents: a 5- or 6-membered heterocycle that contains nitrogen atomby which it is bonded to the ring A and that may contain another heteroatom selected from sulphur, oxygen and nitrogen, a group of formula(II):

wherein R′₁, R′₂, R′₃ and R′₄ may have the same meanings as R₁, R₂, R₃and R₄, respectively, or hydrogen and, in that case, R₄ cannot representunsubstituted phenyl, unsubstituted naphthyl or heteroaryl, R₆represents hydrogen or linear or branched (C₁-C₆)alkyl, the group R₆being present or absent depending on the nature of the ring A,heteroaryl being understood to mean any aromatic, mono- or bi-cyclic, 5-to 10-membered group containing from 1 to 3 hetero atoms selected fromoxygen, nitrogen and sulphur, the term “substituted” used in respect ofthe expressions “phenyl”, “naphthyl” or “heteroaryl” being understood tomean that the groups concerned may be substituted by one or more groups,which may be the same or different, selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, mercapto, linear orbranched (C₁-C₆)-alkylthio, amino, linear or branched (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino in which each alkyl moiety is linear or branched,linear or branched (C₁-C₆)polyhaloalkyl and hydroxy and halogen, itbeing understood that: when R₂ and R₃ together form oxo andsimultaneously R₅ represents hydrogen and R₆ represents hydrogen or doesnot exist, then R₄ is other than phenyl substituted by one groupselected from hydroxy, alkoxy, CF₃ and halogen (except for bromine whenA represents piperidine), or by several groups selected from hydroxy andalkoxy, when R₂ represents hydrogen and R₃ represents hydroxy andsimultaneously R₅ represents hydrogen and R₆ represents hydrogen or doesnot exist, then R₄ is other than phenyl substituted by one groupselected from hydroxy, linear or branched (C₁-C₆)alkoxy, linear orbranched (C₁-C₆)alkyl and chlorine, or by several groups selected fromhydroxy and alkoxy, the compound of formula (I) may not represent1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)ethanol nor2-(2-pyridinyl)cyclohexanone, their enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 2. A compound of formula (I) according to claim 1, wherein thegroup

represents piperidinyl or N-methylpiperidinyl their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 3. A compound of formula (I) according- toclaim 1, wherein the group

represents pyridinyl or N-methylpyridinium their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 4. A compound of formula (I) according to claim1, wherein R₄ represents substituted phenyl, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 5. A compound of formula (I) according to claim1, wherein R₅ represents hydrogen, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 6. A compound of formula (I) according to claim1, wherein R₅ represents a group of formula (II), their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 7. A compound of formula (I) according to claim1, wherein R₂ and R₃ together form oxo, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 8. A compound of formula (I) according to claim1, wherein R₂ represents hydrogen and R₃ represents hydroxy, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 9. A compound of formula (1)according to claim 1 which is1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanone, its enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 10. A compound of formula (I) according toclaim 1 which is(R)-2-1-methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanone and additionsalts thereof with a pharmaceutically acceptable acid or base.
 11. Acompound of formula (I) according to claim 1 which is(S)-2-(1-methyl-2-piperidinyl)-1-(4-bromophenyl)-1-ethanone and additionsalts thereof with a pharmaceutically acceptable acid or base.
 12. Acompound of formula (I) according to claim 1 which is1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol, its enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 13. A compound of formula (I) according toclaim 1 which is(S,S)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol, andaddition salts thereof with a pharmaceutically acceptable acid or base.14. A compound of formula (I) according to claim 1 which is(R,R)-1-(4-bromophenyl)-2-(1-methyl-2-piperidinyl)-1-ethanol, andaddition salts thereof with a pharmaceutically acceptable acid or base.15. A compound of formula (I) according to claim 1 which is1-methyl-2-[2-oxo-2-(4-bromophenyl)ethyl]pyridinium iodide and additionsalts thereof with a pharmaceutically acceptable acid or base.
 16. Amethod for treating a living body afflicted with pain and deficienciesin memory associated with cerebral ageing and with neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Korsakoff'sdisease and frontal lobe and subcortical dementias comprising the stepof administering to the living body an amount of a compound to claims 1to 15 which is effective for the alleviation for said condition.
 17. Apharmaceutical composition useful for treating pain and deficiencies inmemory associated with cerebral ageing and with neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Korsakoff'sdisease and frontal lobe and subcortical dementias comprising, as activeprinciple an effective amount of a compound as claimed in claims 1 to15, together with one or more pharmaceutically acceptable excipients orvehicles.